Alternative Models for Anticancer Drug Discovery From Natural Products Using Binary Tumor‐Microenvironment‐on‐a‐Chip

Abstract The efficacy evaluation of anticancer drugs derived from natural products has traditionally relied on animal models, highlighting the need for more efficient preclinical assessment platforms. In this study, a binary tumor‐microenvironment‐on‐a‐chip (T‐MOC) system is introduced to assess the therapeutic potential of illudin S and roridin E, two cytotoxic compounds derived from Omphalotus japonicus and Podostroma cornu‐damae , respectively. The binary T‐MOC model integrates independently developed vascular and invasive ductal carcinoma compartments, effectively mimicking in vivo drug delivery barriers and physiological dynamics. Using this model, illudin S demonstrates strong anticancer effects but exhibits high toxicity, particularly in the lung and liver, indicating a narrow therapeutic window. Roridin E demonstrates potent activity at low concentrations but exhibits high toxicity, especially in the liver and skin. Additionally, morphological analysis is performed to predict drug delivery and distribution characteristics, revealing anisotropic remission and the influence of microenvironmental factors on drug response. This study underscores the potential of the binary T‐MOC system as an alternative platform for anticancer drug evaluation, enabling efficient preclinical validation while reducing reliance on animal models.